Submitted in response to PAR-11-177, this combined R21/R33 application pairs a dietary supplement intervention intended to target energy metabolism in the brain with translational neuroimaging measures of brain high-energy metabolites that are deficient in mood disorders. Piloting a novel intervention for female adolescents with treatment-resistant major depressive disorder (MDD), while quantifying its engagement of a mechanistic target, supports specific strategies outlined in the strategic plans of the National Institute of Mental Health and the Office of Dietary Supplements. The long-term goal of this research program is to delineate the alterations in mitochondrial brain energy metabolism that are associated with mood disorders. Converging lines of evidence suggest that depression is associated with changes in brain energy metabolism that normalize with resolution of a depressive episode. 31-Phosphorus Magnetic Resonance Spectroscopic Imaging (31P-MRSI), a safe and non-invasive imaging method, allows in vivo measurement of concentrations in specific high-energy cerebral metabolites. These include beta-nucleoside triphosphate (-NTP; largely adenosine triphosphate, or ATP) and phosphocreatine (PCr). 31P-MRSI studies of adults with MDD show a pattern of changes in brain energy metabolism: increased PCr and decreased -NTP. More common in females, this pattern is associated with an increased likelihood of response to both antidepressants in treatment-naive MDD, and thyroid hormone augmentation in treatment-resistant MDD. The organic acid creatine is endogenous to all vertebrates, and is known to play a vital role in maintaining ATP supplies in brain and skeletal muscle. In preclinical animal models, creatine supplementation alters rodent depression-like behaviors in a gender-dependent manner that favors females. In healthy adults, dietary supplementation with creatine increases total brain creatine, and induces the pattern of alterations in PCr and -NTP noted above, suggesting the possibility of using creatine to promote a treatment-responsive state in MDD. In the R21 proof- of-concept study, we propose to test the hypothesis that creatine targets and alters brain energy metabolism in female adolescents selective serotonin reuptake inhibitor (SSRI)-resistant MDD. Participants will be treated for 8 weeks with one of four regimens: placebo or creatine 2g, 4g or 10g daily. 31P-MRSI measurements of PCr and -NTP will be performed at baseline, and repeated after 8 weeks of treatment. If the R21 study milestones are met, we will proceed to an R33 pilot study. Using the dose of creatine that offered the best combination of target engagement and tolerability in the R21 study, a randomized placebo-controlled feasibility study of creatine for adolescent females with SSRI-resistant MDD will be conducted.